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The human coronavirus HCoV-229E S-protein structure and receptor binding.

ABSTRACT: The coronavirus S-protein mediates receptor binding and fusion of the viral and host cell membranes. In HCoV-229E, its receptor binding domain (RBD) shows extensive sequence variation but how S-protein function is maintained is not understood. Reported are the X-ray crystal structures of Class III-V RBDs in complex with human aminopeptidase N (hAPN), as well as the electron cryomicroscopy structure of the 229E S-protein. The structures show that common core interactions define the specificity for hAPN and that the peripheral RBD sequence variation is accommodated by loop plasticity. The results provide insight into immune evasion and the cross-species transmission of 229E and related coronaviruses. We also find that the 229E S-protein can expose a portion of its helical core to solvent. This is undoubtedly facilitated by hydrophilic subunit interfaces that we show are conserved among coronaviruses. These interfaces likely play a role in the S-protein conformational changes associated with membrane fusion.

SUBMITTER: Li Z

PROVIDER: S-EPMC6970540 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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The human coronavirus HCoV-229E S-protein structure and receptor binding.

Li Zhijie Z Tomlinson Aidan Ca AC Wong Alan Hm AH Zhou Dongxia D Desforges Marc M Talbot Pierre J PJ Benlekbir Samir S Rubinstein John L JL Rini James M JM

eLife 20191025

The coronavirus S-protein mediates receptor binding and fusion of the viral and host cell membranes. In HCoV-229E, its receptor binding domain (RBD) shows extensive sequence variation but how S-protein function is maintained is not understood. Reported are the X-ray crystal structures of Class III-V RBDs in complex with human aminopeptidase N (hAPN), as well as the electron cryomicroscopy structure of the 229E S-protein. The structures show that common core interactions define the specificity fo ...[more]

PMID: 31650956

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Project description:Four coronaviruses (HCoV-OC43, HCoV-HKU1, HCoV-NL63, and HCoV-229E) are endemic in human populations. All these viruses are seasonal and generate short-term immunity. Like the highly pathogenic coronaviruses, the endemic coronaviruses have zoonotic origins. Thus, understanding the evolutionary dynamics of these human viruses might provide insight into the future trajectories of SARS-CoV-2 evolution. Because the zoonotic sources of HCoV-OC43 and HCoV-229E are known, we applied a population genetics-phylogenetic approach to investigate which selective events accompanied the divergence of these viruses from the animal ones. Results indicated that positive selection drove the evolution of some accessory proteins, as well as of the membrane proteins. However, the spike proteins of both viruses and the hemagglutinin-esterase (HE) of HCoV-OC43 represented the major selection targets. Specifically, for both viruses, most positively selected sites map to the receptor-binding domains (RBDs) and are polymorphic. Molecular dating for the HCoV-229E spike protein indicated that RBD Classes I, II, III, and IV emerged 3-9 years apart. However, since the appearance of Class V (with much higher binding affinity), around 25 years ago, limited genetic diversity accumulated in the RBD. These different time intervals are not fully consistent with the hypothesis that HCoV-229E spike evolution was driven by antigenic drift. An alternative, not mutually exclusive possibility is that strains with higher affinity for the cellular receptor have out-competed strains with lower affinity. The evolution of the HCoV-OC43 spike protein was also suggested to undergo antigenic drift. However, we also found abundant signals of positive selection in HE. Whereas such signals might result from antigenic drift, as well, previous data showing co-evolution of the spike protein with HE suggest that optimization for human cell infection also drove the evolution of this virus. These data provide insight into the possible trajectories of SARS-CoV-2 evolution, especially in case the virus should become endemic.

Project description:Human seasonal coronaviruses (hCoVs) are a group of viruses that affect the upper respiratory tract. While seasonal patterns and the annual variability of predominant hCoV species are well-documented, their genetic and species diversity in St. Petersburg and across Russia remains largely unexplored. In this study, we developed a two-pool, long-amplicon (900-1100 bp) PCR primer panel for the whole-genome sequencing of four seasonal hCoV species. The panel was validated using nasopharyngeal swab samples collected within the Global Influenza Hospital Surveillance Network (GIHSN) project. Over a period of six epidemiological seasons from 2017 to 2023, we retrospectively analyzed 14,704 nasopharyngeal swabs collected from patients hospitalized in St. Petersburg clinics. Of these samples, 5010 (34.07%) tested positive for respiratory viruses, with 424 (2.88% of all samples) identified as seasonal human coronaviruses. The assessment of species diversity showed that predominant hCoV species alternate between seasons. Whole-genome sequences for 85 seasonal human coronaviruses (hCoVs) with >70% genome coverage were obtained, including 23 hCoV-OC43, 6 hCoV-HKU1, 39 hCoV-229E, and 17 hCoV-NL63. These represent the first near-complete genomes of seasonal hCoVs from the Russian Federation, addressing a significant gap in the genomic epidemiology of these viruses. A detailed phylogenetic analysis of the sequenced genomes was conducted, highlighting the emergence of hCoV-229E subclades 7b.1 and 7b.2, which carry numerous substitutions in the Spike protein. Additionally, we sequenced a historical hCoV-229E isolate collected in the USSR in 1979, the oldest sequenced 229E virus from Eurasia, and demonstrated that it belongs to Genotype 2. The newly developed PCR-based sequencing protocol for seasonal hCoVs is straightforward and well-suited for genomic surveillance, providing a valuable tool to enhance our understanding of the genetic diversity of human seasonal coronaviruses.

Project description:BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has extensively and rapidly spread in the world, causing an outbreak of acute infectious pneumonia. However, no specific antiviral drugs or vaccines can be used. Phillyrin (KD-1), a representative ingredient of Forsythia suspensa, possesses anti-inflammatory, anti-oxidant, and antiviral activities. However, little is known about the antiviral abilities and mechanism of KD-1 against SARS-CoV-2 and human coronavirus 229E (HCoV-229E).PurposeThe study was designed to investigate the antiviral and anti-inflammatory activities of KD-1 against the novel SARS-CoV-2 and HCoV-229E and its potential effect in regulating host immune response in vitro.MethodsThe antiviral activities of KD-1 against SARS-CoV-2 and HCoV-229E were assessed in Vero E6 cells using cytopathic effect and plaque-reduction assay. Proinflammatory cytokine expression levels upon infection with SARS-CoV-2 and HCoV-229E infection in Huh-7 cells were measured by real-time quantitative PCR assays. Western blot assay was used to determine the protein expression of nuclear factor kappa B (NF-κB) p65, p-NF-κB p65, IκBα, and p-IκBα in Huh-7 cells, which are the key targets of the NF-κB pathway.ResultsKD-1 could significantly inhibit SARS-CoV-2 and HCoV-229E replication in vitro. KD-1 could also markedly reduce the production of proinflammatory cytokines (TNF-α, IL-6, IL-1β, MCP-1, and IP-10) at the mRNA levels. Moreover, KD-1 could significantly reduce the protein expression of p-NF-κB p65, NF-κB p65, and p-IκBα, while increasing the expression of IκBα in Huh-7 cells.ConclusionsKD-1 could significantly inhibit virus proliferation in vitro, the up-regulated expression of proinflammatory cytokines induced by SARS-CoV-2 and HCoV-229E by regulating the activity of the NF-кB signaling pathway. Our findings indicated that KD-1 protected against virus attack and can thus be used as a novel strategy for controlling the coronavirus disease 2019.

Dataset Information

The human coronavirus HCoV-229E S-protein structure and receptor binding.

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The human coronavirus HCoV-229E S-protein structure and receptor binding.

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